Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

8-Substituted-2,6-methano-3-benzazocines of general structure I in which
A is --CH2--OH, --CH2NH2, --NHSO2CH3,
##STR00001##
and Y is O, S or NOH are useful as analgesics, anti-diarrheal agents,
anticonvulsants, antitussives and anti-addiction medications.
##STR00002##
8-Carboxamides, thiocarboxamides, hydroxyamidines and formamides are
preferred.

Claims:

1. A method of treating a disease or condition selected from pain,
pruritic, diarrhea, convulsion, cough, anorexia, hyperalgesia, drug
addiction, respiratory depression, dyskinesia, irritable bowel syndrome,
and gastrointestinal motility disorders comprising the step of
administering to a subject in need thereof a compound of formula:
##STR00035## wherein A is ##STR00036## Y is chosen from O and S;
R1 is --NHR8; R2 and R2a are both hydrogen or taken
together R2 and R2a are ═O; R3 is chosen from
hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and
hydroxyalkyl; R4 is chosen from hydrogen, hydroxy, amino, lower
alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted
with hydroxy or carbonyl; R5 is lower alkyl; R6 is lower alkyl;
R7 is chosen from hydrogen and hydroxy; or together R4,
R5, R6 and R7 may form from one to three rings, said rings
having optional additional substitution; and, R8 is hydrogen.

2. The method according to claim 1 wherein: R4 is chosen from
hydrogen, hydroxy, lower alkoxy, C1-C20 alkyl and
C1-C20 alkyl substituted with hydroxy or carbonyl; R5 is
lower alkyl; R6 is lower alkyl; and R7 is hydrogen or hydroxy.

3. The method according to claim 2 wherein: R3 is chosen from
hydrogen, cyclopropyl, cyclobutyl, phenyl, vinyl, dimethylvinyl,
hydroxycyclopropyl, furanyl, and tetrahydrofuranyl; R4 is chosen
from hydrogen and 3-oxo-5-cyclopentyl-l-pentanyl; R5 is methyl; and
R6 is methyl or ethyl.

4. The method according to claim 1 wherein together R5, R6 and
R7 form two rings, said morphinan having the structure:
##STR00037## wherein R4 is hydrogen, hydroxy, amino or lower
alkoxy; R9 is hydrogen or lower alkyl; R10 is chosen from
hydrogen, lower alkyl and hydroxy (lower alkyl); or together, R9 and
R10 form a spiro-fused carbocycle of 5 to 10 carbons; R11 is
hydrogen; R12 is chosen from hydroxy, lower alkoxy, NH2,
--N(CH2CH2Cl)2, and --NHC(O)CH═CHCOOCH3; or
together, R11 and R12 form a carbonyl or a vinyl substituent;
or together, R4 and R11 form a sixth ring.

5. The method according to claim 4, wherein R4 and R11 form a
sixth ring, of formula ##STR00038##

6. The method according to claim 5 wherein R9 is hydrogen; R10
is hydroxy (lower alkyl); and R12 is lower alkoxy.

7. The method according to claim 4, wherein R11 and R12 form a
carbonyl substituent, of formula: ##STR00039##

8. The method according to claim 7 wherein R2 and R2a are both
hydrogen; R4 is chosen from hydrogen, hydroxy, amino and lower
alkoxy; and R9 and R10 are both hydrogen or together, R9
and R10 form a spiro-fused carbocycle of 5 to 10 carbons.

9. The method according to claim 8 wherein R9 and R10 are both
hydrogen.

10. The method according to claim 4, wherein R11 and R12 form a
vinyl substituent, of formula: ##STR00040##

11. The method according to claim 10 wherein R2 and R2a are
both hydrogen; R4 is hydroxy; and R9 and R10 are both
hydrogen.

12. The method according to claim 4 wherein R2 and R2a are both
hydrogen; R4 is hydroxy; R9 and R10 are both hydrogen; and
R12 is chosen from: --NH2, --N(CH2CH2Cl)2, and
--NHC(O)CH═CHCOOCH.sub.3.

13. The method according to claim 1 wherein together R5, R6 and
R7 form two rings of formula: ##STR00041##

14. The method according to claim 4 wherein R4 and R11 form a
sixth ring, of formula ##STR00042## wherein R9 is hydrogen;
R10 is hydroxy (lower alkyl); and R12 is lower alkoxy.

16. The method of claim 15 wherein the morphinan compound has the
formula: ##STR00043## Wherein, R2 and R2a are both hydrogen;
R4 is hydroxyl; and, R9 and R10 are both hydrogen.

17. The method according to claim 15 wherein the drug addiction is
heroin, cocaine, nicotine or alcohol addiction.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of copending U.S. application Ser.
No. 13/103,599, filed May 9, 2011, now allowed, which was a continuation
of U.S. application Ser. No. 12/249,238, filed Oct. 10, 2008, now U.S.
Pat. No. 7,956,187, which was a divisional of U.S. application Ser. No.
11/205,354, filed Aug. 17, 2005, now abandoned, which was a divisional of
U.S. application Ser. No. 10/987,527, filed Nov. 12, 2004, now U.S. Pat.
No. 7,265,226, which was a divisional of U.S. application Ser. No.
10/409,803, filed Apr. 9, 2003, now U.S. Pat. No. 6,887,998, which was a
divisional of Ser. No. 10/305,287, filed Nov. 26, 2002, now U.S. Pat. No.
6,784,187. U.S. Ser. No. 10/305,287 was a continuation-in-part of PCT
International Application PCT/US01/045581, filed Oct. 31, 2001, and
published under PCT Article 21(2) in English as WO 02/36573 on May 10,
2002. PCT/US01/045581 claimed benefit from U.S. Provisional Application
60/244,438, filed Oct. 31, 2000. The entire contents of each of the prior
applications are incorporated herein by reference.

[0004] Opiates have been the subject of intense research since the
isolation of morphine in 1805, and thousands of compounds having opiate
or opiate-like activity have been identified. Many opioid
receptor-interactive compounds including those used for producing
analgesia (e.g., morphine) and those used for treating drug addiction
(e.g., naltrexone and cyclazocine) in humans have limited utility due to
poor oral bioavailability and a very rapid clearance rate from the body.
This has been shown in many instances to be due to the presence of the
8-hydroxyl group (OH) of 2,6-methano-3-benzazocines, also known as
benzomorphans [(e.g., cyclazocine and EKC (ethylketocyclazocine)] and the
corresponding 3-OH group in morphinanes (e.g., morphine).

##STR00003##

The high polarity of these hydroxyl groups retards oral absorption of the
parent molecules. Furthermore, the 8-(or 3-)OH group is prone to
sulfonation and glucuronidation (Phase II metabolism), both of which
facilitate rapid excretion of the active compounds, leading to
disadvantageously short half-lives for the active compounds.
Unfortunately, the uniform experience in the art of the past seventy
years has been that removal or replacement of the 8-(or 3-)OH group has
lead to pharmacologically inactive compounds.

SUMMARY OF THE INVENTION

[0005] We have now found that the 8-(or 3-)hydroxyl group may be replaced
by a number of small, polar, neutral residues, such as carboxamide,
thiocarboxamide, hydroxyamidine and formamide groups. Not only do the
benzomorphan, morphinan carboxamides have unexpectedly high affinity for
opioid receptors, compounds containing these groups in place of OH are
far less susceptible to Phase II metabolism and are generally more orally
bioavailable. The compounds of the invention are therefore useful as
analgesics, anesthetics, anti-pruritics, anti-diarrheal agents,
anticonvulsants, antitussives, anorexics and as treatments for
hyperalgesia, drug addiction, respiratory depression, dyskinesia, pain
(including neuropathic pain), irritable bowel syndrome and
gastrointestinal motility disorders. Drug addiction, as used herein,
includes alcohol and nicotine addiction. There is evidence in the
literature that the compounds may also be useful as anti-retroviral
agents, immunosuppressants and antiinflammatories and for reducing
ischemic damage (and cardioprotection), for improving learning and
memory, and for treating urinary incontinence.

[0006] In one aspect, the invention relates to
2,6-methano-3-benzazocine-8-carboxamides and
2,6-methano-3-benzazocine-8-carboxylate esters of formula:

##STR00004##

wherein [0007] A is chosen from --CH2--Z, --CN,
--NHSO2-(loweralkyl),

[0007] ##STR00005## [0008] Q is chosen from O, S and NR17; [0009]
Y is chosen from O, S, NR17 and NOH; [0010] Z is chosen from OH, SH,
CN and NH2; [0011] R1 is chosen from hydrogen, lower alkoxy,
phenyl and --NHR8; [0012] R2 and R2a are both hydrogen or
taken together R2 and R2a are ═O; [0013] R3 is chosen
from hydrogen, lower alkyl, alkenyl, aryl, heterocyclyl, benzyl and
hydroxyalkyl; [0014] R4 is chosen from hydrogen, hydroxy, amino,
lower alkoxy, C1-C20 alkyl and C1-C20 alkyl
substituted with hydroxy or carbonyl; [0015] R5 is lower alkyl;
[0016] R6 is lower alkyl; [0017] R7 is chosen from hydrogen and
hydroxy; or [0018] together R4, R5, R6 and R7 may
form from one to three rings, said rings having optional additional
substitution; [0019] R8 is chosen from hydrogen, --OH, --NH2
and --CH2R15; [0020] R15 is chosen from hydrogen, alkyl,
aryl, substituted aryl and alkyl substituted with alkoxy, amino,
alkylamino or dialkylamino; [0021] R16 is chosen from hydrogen and
NH2; and [0022] R17 is chosen from hydrogen, alkyl, aryl and
benzyl; [0023] with the provisos that, (1) when R2 and R2a are
hydrogen, R3 is hydrogen or cyclopropyl, R4 is hydroxy, and
together R5, R6 and R7 form two rings substituted with a
spirodioxolane, A cannot be --COOCH3 or NHSO2CH3; (2) when
R2 and R2a are hydrogen, R3 is hydrogen or cyclopropyl,
R4 is hydroxy, and together R5, R6 and R7 form the
ring system of oxymorphone and naltrexone, A cannot be
NHSO2CH3; (3) when R2, R2a, R4 and R7 are
hydrogen, R3 is cyclopropyl and R5 and R6 are methyl, A
cannot be --NHC(O)H. The explicit provisos exclude oxymorphone and
naltrexone-3-sulfonamides, which were disclosed as having no activity in
vitro or in vivo [McCurdy et al. Org. Lett. 2, 819-821 (2000)]; and
cyclazocine formamide, which was disclosed as an intermediate in a
synthesis in U.S. Pat. Nos. 3,957,793; 4,032,529 and 4,205,171.
Additionally, when A is --CN, R7 must be hydroxyl. When R4,
R5, R6, and R7 form one to three rings, it is preferred
that none of the rings formed by R4, R5, R6, and R7
is aryl or heteroaryl.

[0024] Subclasses of the foregoing structure include: [0025] II.
2,6-methano-3-benzazocines of the structure shown above, in which
R4, R5, R6 and R7 do not form additional rings;
[0026] III. morphinans in which R5 and R6 form one ring:

[0026] ##STR00006## [0027] IV. morphinans in which R5, R6 and
R7 form two rings:

##STR00007##

[0027] and [0028] V. morphinans wherein R4 and R11 form an
additional sixth ring, which may be saturated or unsaturated (but not
fully aromatic):

##STR00008##

[0028] In addition to the major subclasses, there are compounds such as

##STR00009##

which the person of skill recognizes as closely related to the major
subclasses, but which defy easy description in a common Markush
structure.

[0029] In another aspect, the invention relates to a method for preparing
a second compound that interacts with an opioid receptor when a first
compound that interacts with an opioid receptor is known. When the first
compound contains a phenolic hydroxyl, the method comprises converting
the phenolic hydroxyl to a residue chosen from the group described as the
variable A above.

[0030] In another aspect, the invention relates to a method for decreasing
the rate of metabolism of a compound that interacts at an opioid
receptor. When the first compound contains a phenolic hydroxyl, the
method comprises converting the phenolic hydroxyl to a residue chosen
from the group described as the variable A above.

[0031] In another aspect, the invention relates to methods for inhibiting,
eliciting or enhancing responses mediated by an opioid receptor
comprising: [0032] (a) providing a first compound that inhibits, elicits
or enhances an opioid receptor response; [0033] (b) preparing a second
compound that interacts with an opioid receptor by converting a phenolic
hydroxyl group on the first compound to a residue described as A above;
and [0034] (c) bringing the second compound into contact with the opioid
receptor.

[0035] In another aspect, the invention relates to a method for treating a
disease by altering a response mediated by an opioid receptor. The method
comprises bringing into contact with the opioid receptor a compound
having the formula

##STR00010##

wherein B represents the appropriate residue of a known compound of
formula

##STR00011##

and the known compound of that formula alters a response mediated by an
opioid receptor.

[0036] In another aspect, the invention relates to processes for
converting opioid-binding phenols or phenols on a benzomorphan or
morphinan to a carboxamide. The carboxamide conversion processes comprise
either: [0037] (a) reacting the phenol with a reagent to convert it to a
group displaceable by CN.sup.θ; [0038] (b) reacting that group with
Zn(CN)2 in the presence of a Pd(0) catalyst to provide a nitrile;
and [0039] (c) hydrolyzing the nitrile to a carboxamide; or: [0040] (a)
reacting the phenol with a reagent to convert the phenol to a triflate;
[0041] (b) reacting the triflate with carbon monoxide and ammonia in the
presence of a Pd(II) salt and a Pd(0) catalyst to provide a carboxamide;
or [0042] (a) reacting the phenol with a reagent to convert the phenol to
a triflate; [0043] (b) reacting the triflate with carbon monoxide and
hexamethyldisilazane in the presence of a Pd(II) salt and a Pd(0)
catalyst to provide a silylated carboxamide precursor; and [0044] (c)
hydrolyzing the silylated carboxamide precursor to provide a carboxamide.

[0045] Similar processes convert phenols to amidines and thioamides by
reacting the foregoing nitrile with hydroxylamine to produce a
hydroxyamidine or reacting the foregoing carboxamide with a pentavalent
phosphorus-sulfur reagent to produce a thioamide. For the purpose of the
invention an "opioid-binding phenol" is one that exhibits binding at an
opioid receptor below 25 nM.

DETAILED DESCRIPTION OF THE INVENTION

[0046] From many years of SAR studies, it is known that the hydroxyl of
morphinans and benzomorphans interacts with a specific site in the opiate
receptor. Previous exploration of the tolerance of this site for
functional groups other than phenolic hydroxyls has almost uniformly
resulted in the complete or near-complete loss of opioid binding. We have
now surprisingly found that the hydroxyl can be replaced with one of
several bioisosteres. Although a fairly wide range of primary and
secondary carboxamides, as well as carboxylates, aminomethyl,
hydroxymethyl and even dihydroimidazolyl exhibit binding in the desired
range below 25 nanomolar, optimal activity is observed with a
carboxamido, thiocarboxamido, hydroxyamidino or formamido group.

[0047] Since the hydroxyl functionality of benzomorphans and morphinans
can be chemically converted to an amide by a simple, flexible and
convenient route described below, and since thiocarboxamido,
hydroxyamidino and formamido compounds are also easily synthesized as
described below, the door is opened to improving the bioavailability of
virtually any of the known and new therapeutic agents that rely on opioid
binding for their activity. Moreover, since the receptor seems to
tolerate some variation beyond the α-carbon of A, one may
contemplate further modulating receptor specificity, affinity and tissue
distribution by varying the properties of the alkyl or aryl substituents
on A. Preferred residues A are --COOCH3, --COOEt, --CONH2,
--C(═S)NH2, --C(O)NHOH, --C(O)NHNH2, --CONHCH3,
--CONHBn, --CONHCH2(4-MeOC6H4), 2-(4,5-dihydroimidazolyl),
--C(═NOH)NH2, --CH2NH2, CH2OH,
--COC6H5, --C(═NOH)C6H5, --NHCHO, --NHCHS and
--NHSO2CH3. When R7 is hydroxyl, A may also be --CN. Most
preferred are --CONH2, --C(═S)NH2, --C(═NOH)NH2,
and --NHCHO.

[0048] It is known in the art that compounds that are μ, δ and
κ agonists exhibit analgesic activity; compounds that are selective
μ agonists exhibit anti-diarrheal activity and are useful in treating
dyskinesia; μ antagonists and κ agonists are useful in treating
heroin, cocaine, alcohol and nicotine addiction; κ agonists are
also anti-pruritic agents and are useful in treating hyperalgesia.
Recently it has been found [Peterson et al. Biochem. Pharmacol. 61,
1141-1151 (2001)] that κ agonists are also useful in treating
retroviral infections. In general, the dextrorotatory isomers of
morphinans of type III above are useful as antitussives and
anticonvulsants. Additional diseases and conditions for which opioid
agonists and antagonists are known to be useful include irritable bowel
syndrome, gastrointestinal motility disorder, obesity and respiratory
depression. Certain opioids (e.g. fentanyl and derivatives) are useful as
anesthetics, i.e., they alter the state of consciousness.

[0049] Opioid receptor ligands having known high affinity are shown in the
following charts 1 and 2. Replacement of OH in these compounds produces
compounds that exhibit similar activity and better bioavailability.

##STR00012## ##STR00013##

##STR00014## ##STR00015## ##STR00016## ##STR00017##

##STR00018## ##STR00019## ##STR00020##

Other opioid receptor ligands are described in Aldrich, J. V.
"Analgesics" in Burger's Medicinal Chemistry and Drug Discovery, M. E.
Wolff ed., John Wiley & Sons 1996, pages 321-44, the disclosures of which
are incorporated herein by reference.

[0050] We have examined the opioid receptor binding of a series of analogs
of known compounds that interact at opioid receptors in which the OH is
replaced by the R-group shown in Tables 1-4. The standards are shown in
Table 5. The affinities of the compounds of the invention were determined
in guinea pig brain cells by the method described in Wentland et al.
Biorgan. Med. Chem. Lett. 9. 183-187 (2000). Alternatively, where noted,
the affinities of the compounds of the invention were determined in
cloned human receptors in Chinese hamster ovary cells by the method
described by Xu et al [Synapse 39, 64-69 (2001)]. CHO cell membranes,
expressing the human μ, δ, or κ opioid receptor, were
incubated with 12 different concentrations of the compounds in the
presence of receptor-specific radioligands at 25° C., in a final
volume of 1 ml of 50 mM Tris-HCl, pH 7.5. Nonspecific binding was
determined using 1 μM naloxone. Data are the mean value±S.E.M. from
three experiments, performed in triplicate.

Example 4 was tested several times independently to confirm the
Ki's. Inspection of the results in Table 1 indicates not only that
affinity is preserved in the compounds of the invention, but also that
receptor selectivity can be modulated.

[0051] Antinociceptive activity is evaluated by the method described in
Jiang et al. [J. Pharmacol. Exp. Ther. 264, 1021-1027 (1993), page 1022].
Compound 4 was found to exhibit an ED50 of 0.21 nmol in the mouse
acetic acid writhing test when administered i.c.v. Its "parent"
cyclazocine exhibited an ED50 of 2.9 nmol i.c.v. The time courses in
producing antinociception in the mouse writhing test were compared for
compound 4 and cyclazocine. Mice were injected with 1.0 mg/kg of either
compound 4 or cyclazocine, given by i.p. administration. An increase in
the duration of action from ca. 2 hr to 15 hr was observed for compound 4
compared to cyclazocine.

Definitions

[0052] Throughout this specification the terms and substituents retain
their definitions.

[0053] Alkyl is intended to include linear, branched, or cyclic
hydrocarbon structures and combinations thereof. Lower alkyl refers to
alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups
include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, s-and
t-butyl, cyclobutyl and the like. Preferred alkyl groups are those of
C20 or below. Cycloalkyl is a subset of alkyl and includes cyclic
hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl
groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.

[0054] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a
straight, branched, cyclic configuration and combinations thereof
attached to the parent structure through an oxygen. Examples include
methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and
the like. Lower-alkoxy refers to groups containing one to four carbons.

[0056] Arylalkyl means an alkyl residue attached to an aryl ring. Examples
are benzyl, phenethyl and the like. Heteroarylalkyl means an alkyl
residue attached to a heteroaryl ring. Examples include, e.g.,
pyridinylmethyl, pyrimidinylethyl and the like.

[0057] Heterocycle means a cycloalkyl or aryl residue in which one to two
of the carbons is replaced by a heteroatom such as oxygen, nitrogen or
sulfur. Heteroaryls form a subset of heterocycles. Examples of
heterocycles that fall within the scope of the invention include
pyrrolidine, pyrazole, pyrrole, indole, quinoline, isoquinoline,
tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly
referred to as methylenedioxyphenyl, when occurring as a substituent),
tetrazole, morpholine, thiazole, pyridine, pyridazine, pyrimidine,
thiophene, furan, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran
and the like.

[0059] Virtually all of the compounds described herein contain one or more
asymmetric centers and may thus give rise to enantiomers, diastereomers,
and other stereoisomeric forms that may be defined, in terms of absolute
stereochemistry, as (R)-- or (S)--. The present invention is meant to
include all such possible isomers, as well as their racemic and optically
pure forms. In general it has been found that the levo isomer of
morphinans and benzomorphans is the more potent antinociceptive agent,
while the dextro isomer may be useful as an antitussive or antispasmodic
agent. Optically active (R)-- and (S)-- isomers may be prepared using
chiral synthons or chiral reagents, or resolved using conventional
techniques. When the compounds described herein contain olefinic double
bonds or other centers of geometric asymmetry, and unless specified
otherwise, it is intended that the compounds include both E and Z
geometric isomers. Likewise, all tautomeric forms are also intended to be
included.

[0105] In the general processes described below, the preferred reagent to
convert a phenol to a group displaceable by CN.sup.θ is
trifluoromethansulfonic anhydride, which is usually employed in the
presence of base. Other reagents are known to persons of skill in the art
to convert phenols to groups that may be displaced by cyanide anion. The
advantage of the trifluoromethansulfonic anhydride procedure is that it
allows displacement under conditions that are mild enough to avoid
destruction of the rest of the molecule for most species of interest.
Other reagents are operable, but require more robust substrates than may
be of interest in a particular case. The consideration of which to use is
within the skill of the artisan. A preferred Pd(0) catalyst for use in
the displacement with zinc cyanide is
tetrakis(triphenylphosphine)palladium. In the direct displacements with
carbon monoxide and ammonia or an ammonia equivalent, the preferred Pd(0)
catalyst is generated in situ from Pd(OAc)2 or PdCl2 and
1,1'-bis(diphenylphosphino)ferrocene. Other Pd(0) ligands include DPPF,
DPPP, triphenylphosphine, 1,3-bis(diphenylphosphino)propane, BINAP and
xantphos. The preferred pentavalent phosphorus-sulfur reagents for
converting carboxamides to thiocarboxamides are Lawesson's reagent and
phosphorus pentasulfide.

[0106] It may happen that residues in the substrate of interest require
protection and deprotection during the conversion of the phenol to the
desired bioisostere. Terminology related to "protecting", "deprotecting"
and "protected" functionalities occurs throughout this application. Such
terminology is well understood by persons of skill in the art and is used
in the context of processes which involve sequential treatment with a
series of reagents. In that context, a protecting group refers to a group
which is used to mask a functionality during a process step in which it
would otherwise react, but in which reaction is undesirable. The
protecting group prevents reaction at that step, but may be subsequently
removed to expose the original functionality. The removal or
"deprotection" occurs after the completion of the reaction or reactions
in which the functionality would interfere. Thus, when a sequence of
reagents is specified, as it is in the processes of the invention, the
person of ordinary skill can readily envision those groups that would be
suitable as "protecting groups". Suitable groups for that purpose are
discussed in standard textbooks in the field of chemistry, such as
Protective Groups in Organic Synthesis by T. W. Greene [John Wiley &
Sons, New York, 1991], which is incorporated herein by reference.

[0107] The compounds of the invention are synthesized by one of the routes
described below:

##STR00032##

##STR00033##

##STR00034##

Chemical Syntheses

[0108] Proton NMR [Varian Unity-500 (500 MHz) NMR] data, direct insertion
probe (DIP) chemical ionization mass spectra (Shimadzu GC-17A GC-MS mass
spectrometer), and infrared spectra (Perkin-Elmer Paragon 1000 FT-IR
spectrophotometer) were consistent with the assigned structures of all
test compounds and intermediates. 1H NMR multiplicity data are
denoted by s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br (broad). Coupling constants are in hertz. Carbon,
hydrogen, and nitrogen elemental analyses for all novel targets were
performed by Quantitative Technologies Inc., Whitehouse, N.J., and were
within ±0.4% of theoretical values except as noted; the presence of
water was conformed by proton NMR. Melting points were determined on a
Meltemp capillary melting point apparatus and are uncorrected. Optical
rotation data were obtained from a Perkin-Elmer 241 polarimeter.
Reactions were generally performed under a N2 atmosphere. Amines
used in the Pd-catalyzed amination reactions and
racemic-2,2'-bis(diphenylphosphino)-1,1'-binapthyl (BINAP) were purchased
from Aldrich Chemical Company and used as received unless otherwise
indicated. Tris(dibenzylideneacetone) dipalladium (0)
[Pd2(dba)3], Pd(OAc)2,
1,1'-bis(diphenylphosphino)ferrocene (DPPF), were purchased from Strem
Chemicals, Incorporated. Toluene and Et2O were distilled from sodium
metal. THF was distilled from sodium/benzophenone ketyl. Pyridine was
distilled from KOH. Methylene chloride was distilled from CaH2. DMF
and DMSO were distilled from CaH2 under reduced pressure. Methanol
was dried over 3± molecular sieves prior to use. Silica gel (Bodman
Industries, ICN SiliTech 2-63 D 60A, 230-400 Mesh) was used for flash
column chromatography.

[0111] (±)-3-(Cyclopropylmethyl)-1,2,3,4,5,6-hexahydro-cis-6,11-dimethy-
l-2,6-methano-3-benzazocin-8-carboxamide [1] (alternate procedure). A
flask containing triflate 36 (100 mg), Pd(OAc)2 (10.2 mg), and
1,1'-bis(diphenylphosphino)ferrocene(DPPF, 25 mg) was purged with argon.
The argon was replaced with gaseous CO and the reaction vessel was closed
to the atmosphere. Dry DMSO (1.25 mL) was added via syringe and gaseous
ammonia was added to the resulting mixture via a canula. A balloon was
used to keep the additional volume contained. The mixture was stirred for
17 h at 70° C. followed by cooling to 25° C. The reaction
mixture was diluted with water and the product was extracted into ethyl
acetate. The organic extracts was washed with aqueous NaHCO3 and
dried (Na2SO4). Concentration of the solvent in vacuo gave 90
mg of a crude product. This material was purified via flash
chromatography (25:1:0.1--CH2Cl2:MeOH:conc NH4OH) to
provide 47 mg (65.3%) of compound 4.

[0118] The remaining compounds of Table 1 were prepared in similar
fashion, except Example 8, which was made by the CO/palladium route, but
with a slight variation using 2.0 M CH3NH2 in THF, rather than
gaseous CH3NH2, and DMF rather than DMSO; mp=155-156°
C.; 25.6% yield. 24--[the (±)-8-CONH2 analogue of
ethylketocyclazocine (R2 and R2a═O; R6═Et)] was
made by the nitrile hydrolysis route, mp=194-196° C.; Step
1--89.1%, Step 2--81.4%. 23--[the (±)-8-CONH2 analogue of
ketocyclazocine (R2 and R2a═O; R6=Me)] was made by the
nitrile hydrolysis route, mp=206-207° C.; Step 1--99.7%, Step
2--94.2%. It was also made by the CO/Pd route in 34.7% yield.

[0119] In general, the chemistry described above works in the presence of
the variety of functional groups found on known core structures. The
exceptions would be morphine and congeners having a free 6-OH, which can
be protected by a TBDPS (t-butyldiphenylsilyl) group [see Wentland et al
J. Med. Chem. 43, 3558-3565 (2000)].

[0120] The compound identified as Example 43 in table 4 was prepared by
treating the nitrile of nalbuphine with an excess of potassium hydroxide
in t-butanol as described for example 4 above. Hydrolysis of the nitrile
appears to have proceeded more slowly than elimination and ring opening.

[0121] Although this invention is susceptible to embodiment in many
different forms, preferred embodiments of the invention have been shown.
It should be understood, however, that the present disclosure is to be
considered as an exemplification of the principles of this invention and
is not intended to limit the invention to the embodiments illustrated. It
may be found upon examination that certain members of the claimed genus
are not patentable to the inventors in this application. In this event,
subsequent exclusions of species from the compass of applicants' claims
are to be considered artifacts of patent prosecution and not reflective
of the inventors' concept or description of their invention; the
invention encompasses all of the members of the genus (I) that are not
already in the possession of the public.

Patent applications by Mark P. Wentland, Watervliet, NY US

Patent applications by Rensselaer Polytechnic Institute

Patent applications in class One of the five cyclos is five-membered and includes ring chalcogen (e.g., codeine, morphine, etc.)

Patent applications in all subclasses One of the five cyclos is five-membered and includes ring chalcogen (e.g., codeine, morphine, etc.)